Compounds for the treatment of neurodegenerative diseases

ABSTRACT

Disclosed herein are compounds for the treatment of neurodegenerative diseases and compositions comprising the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/240,673, filed Jan. 4, 2019, which claims priority to U.S.Provisional Patent Application No. 62/614,204, filed Jan. 5, 2018, whichare incorporated herein by reference in their entirety.

FIELD

This disclosure relates to compounds, as well as methods andcompositions comprising the same, for the treatment of neurodegenerativediseases.

INTRODUCTION

Neurodegeneration is the progressive loss of structure or function ofneurons, including death of neurons. Many neurodegenerative diseasesoccur as a result of neurodegenerative processes. Such diseases arecurrently incurable, resulting in progressive degeneration, cognitiveimpairment, and/or death of neuron cells. An emerging number ofneurodegenerative diseases continue to impact human health. The exactnumber of neurodegenerative diseases remains elusive, yet estimatesproject 600 brain disorders impacting 50 million Americans and costingin excess of $5 billion according to the National Institutes of Health.There is a need for new and effective therapies to treatneurodegenerative diseases.

SUMMARY

In an aspect, the disclosure relates to a compound selected from thefollowing:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the disclosure relates to a pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable saltthereof as detailed herein, and a carrier.

Another aspect of the disclosure provides a method of treating aneurodegenerative disease in a subject. The method may includeadministering to the subject a compound or pharmaceutically acceptablesalt thereof as detailed herein or a composition comprising the same.

In some embodiments, the neurodegenerative disease is selected fromAlzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS),Parkinson's Disease (PD), Huntington's Disease, prion disease, motorneuron disease, spinocerebellar ataxia, spinal muscular atrophy,neuronal loss, cognitive defect, primary age-related tauopathy(PART)/Neurofibrillary tangle-predominant senile dementia, chronictraumatic encephalopathy including dementia pugilistica, dementia withLewy bodies, neuroaxonal dystrophies, and multiple system atrophy,progressive supranuclear palsy, Pick's Disease, corticobasaldegeneration, some forms of frontotemporal lobar degeneration,frontotemporal dementia and parkinsonism linked to chromosome 17,Lytico-Bodig disease (Parkinson-dementia complex of Guam),ganglioglioma, gangliocytoma, meningioangiomatosis, postencephaliticparkinsonism, subacute sclerosing panencephalitis, lead encephalopathy,tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis. Insome embodiments, the neurodegenerative disease is selected fromAlzheimer's Disease (AD) and Huntington's Disease.

Another aspect of the disclosure provides a method of reducing oreliminating an aggregated protein in a subject. The method may includeadministering to the subject a compound or pharmaceutically acceptablesalt thereof as detailed herein or a composition comprising the same,wherein the aggregated protein comprises at least one of tau, synuclein,amyloid-beta, or a combination thereof. In some embodiments, thesynuclein comprises alpha-synuclein.

Another aspect of the disclosure provides a method of reducing orinhibiting protein aggregation in a subject. The method may includeadministering to the subject an effective amount of a compound orpharmaceutically acceptable salt thereof as detailed herein or acomposition comprising the same, wherein the protein comprises at leastone of tau, synuclein, amyloid-beta, or a combination thereof. In someembodiments, the synuclein comprises alpha-synuclein.

The disclosure provides for other aspects and embodiments that will beapparent in light of the following detailed description and accompanyingfigures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the structure of an α-peptide and a γ-AApeptide.

FIG. 2 is a schematic diagram of the synthesis of γ-AApeptides.

FIG. 3 is a schematic diagram of N-Alloc protected γ-AApeptide buildingblocks and acylating agents (carboxylic acids and acyl chlorides) thatmay be used in the preparation of γ-AApeptides.

FIG. 4 is a graph of ThT assay results showing the effect of HW-C-9 onamyloid-beta (Aβ) aggregates.

FIG. 5 is a graph of ThT assay results showing the effect of HW-C-9 onTau protein aggregates.

FIG. 6A and FIG. 6B are the results of assays to examine the effect ofHW-C-9 on the aggregation of Aβ42. FIG. 6A is a Western blot of Aβ42alone, Aβ42 with HW-155-1, or Aβ42 with HW-C-9. FIG. 6B (left) is animage of Aβ42 in mouse brain tissue with or without incubation withHW-C-9. FIG. 6B (right) is a graph of the quantification of the densityand strength of Aβ42 staining in FIG. 6B (left).

FIG. 7 is a Western blot of human recombinant alpha-synuclein withoutaggregation, human recombinant alpha-synuclein with aggregation, andhuman recombinant alpha-synuclein with aggregation but in the presenceof HW-C-9.

DETAILED DESCRIPTION

Described herein are compounds that inhibit or disrupt the aggregationof peptides. The compounds may inhibit or reduce the aggregation ofpeptides such as, for example, aggregates of tau, synuclein, and/oramyloid-beta. Accordingly, the compounds as detailed herein may be usedto treat neurodegenerative diseases.

1. DEFINITIONS

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. In case of conflict, the present document, includingdefinitions, will control. Preferred methods and materials are describedbelow, although methods and materials similar or equivalent to thosedescribed herein can be used in practice or testing of the presentinvention. All publications, patent applications, patents and otherreferences mentioned herein are incorporated by reference in theirentirety. The materials, methods, and examples disclosed herein areillustrative only and not intended to be limiting.

The terms “comprise(s),” “include(s),” “having,” “has,” “can,”“contain(s),” and variants thereof, as used herein, are intended to beopen-ended transitional phrases, terms, or words that do not precludethe possibility of additional acts or structures. The singular forms“a,” “and,” and “the” include plural references unless the contextclearly dictates otherwise. The present disclosure also contemplatesother embodiments “comprising,” “consisting of,” and “consistingessentially of,” the embodiments or elements presented herein, whetherexplicitly set forth or not.

For the recitation of numeric ranges herein, each intervening numberthere between with the same degree of precision is explicitlycontemplated. For example, for the range of 6-9, the numbers 7 and 8 arecontemplated in addition to 6 and 9, and for the range 6.0-7.0, thenumber 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 areexplicitly contemplated.

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing the invention (especiallyin the context of the following claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The use of the term “at least one”followed by a list of one or more items (for example, “at least one of Aand B”) is to be construed to mean one item selected from the listeditems (A or B) or any combination of two or more of the listed items (Aand B), unless otherwise indicated herein or clearly contradicted bycontext.

The term “about” as used herein as applied to one or more values ofinterest, refers to a value that is similar to a stated reference value.The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (forexample, it includes at least the degree of error associated with themeasurement of the particular quantity). The modifier “about” shouldalso be considered as disclosing the range defined by the absolutevalues of the two endpoints. For example, the expression “from about 2to about 4” also discloses the range “from 2 to 4.” The term “about” mayrefer to plus or minus 10% of the indicated number. For example, “about10%” may indicate a range of 9% to 11%, and “about 1” may mean from0.9-1.1. Other meanings of “about” may be apparent from the context,such as rounding off, so, for example “about 1” may also mean from 0.5to 1.4. In certain aspects, the term “about” refers to a range of valuesthat fall within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%,9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greaterthan or less than) of the stated reference value unless otherwise statedor otherwise evident from the context (except where such number wouldexceed 100% of a possible value).

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this disclosure, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito, 1999; Smith and March March's Advanced OrganicChemistry, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Larock,Comprehensive Organic Transformations, VCH Publishers, Inc., New York,1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd)Edition, Cambridge University Press, Cambridge, 1987; the entirecontents of each of which are incorporated herein by reference.

The term “alkoxy” or “alkoxyl” as used herein, refers to an alkyl group,as defined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of alkoxy include, but are notlimited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 20 carbon atoms. The term “loweralkyl” or “C₁-C₆ alkyl” means a straight or branched chain hydrocarboncontaining from 1 to 6 carbon atoms. The term “C₁-C₄ alkyl” means astraight or branched chain hydrocarbon containing from 1 to 4 carbonatoms. The term “C₁-C₃ alkyl” means a straight or branched chainhydrocarbon containing from 1 to 3 carbon atoms. Representative examplesof alkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkenyl” as used herein, means an unsaturated hydrocarbonchain containing from 2 to 20 carbon atoms and at least onecarbon-carbon double bond.

The term “alkynyl” as used herein, means an unsaturated hydrocarbonchain containing from 2 to 20 carbon atoms and at least onecarbon-carbon triple bond.

The term “alkoxyalkyl” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through analkylene group, as defined herein.

The term “arylalkyl” as used herein, refers to an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein.

The term “alkylamino,” as used herein, means at least one alkyl group,as defined herein, is appended to the parent molecular moiety through anamino group, as defined herein.

The term “alkylene” as used herein, refers to a divalent group derivedfrom a straight or branched chain hydrocarbon of 1 to 10 carbon atoms,for example, of 2 to 5 carbon atoms. Representative examples of alkyleneinclude, but are not limited to, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,and —CH₂CH₂CH₂CH₂CH₂—.

The term “amide,” as used herein, means —C(O)NR— or —NRC(O)—, wherein Rmay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle,alkenyl, or heteroalkyl.

The term “aminoalkyl,” as used herein, means at least one amino group,as defined herein, is appended to the parent molecular moiety through analkylene group, as defined herein.

The term “amino” as used herein, means —NR_(x)R_(y), wherein R_(x) andR_(y) may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle,alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any othermoiety where amino appends together two other moieties, amino may be—NR_(x)—, wherein R_(x) may be hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, heterocycle, alkenyl, or heteroalkyl.

The term “aryl” as used herein, refers to an aromatic group such as aphenyl group, or a bicyclic fused ring system. Bicyclic fused ringsystems are exemplified by a phenyl group appended to the parentmolecular moiety and fused to a cycloalkyl group, as defined herein, aphenyl group, a heteroaryl group, as defined herein, or a heterocycle,as defined herein. Representative examples of aryl include, but are notlimited to, indolyl, naphthyl, phenyl, quinolinyl, andtetrahydroquinolinyl.

The term “carboxyl” as used herein, means a carboxylic acid, or —COOH.

The term “cycloalkyl” means a monovalent saturated hydrocarbon ring or abicyclic group. Cycloalkyl groups have zero heteroatoms and zero doublebonds. Cycloalkyl groups are monocyclic, or are fused, spiro, or bridgedbicyclic ring systems. Monocyclic cycloalkyl groups contain 3 to 10carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6carbon atoms in the ring. Bicyclic cycloalkyl groups contain 8 to 12carbon atoms, preferably 9 to 10 carbon atoms in the ring. Cycloalkylgroups may be substituted or unsubstituted. Cycloalkyl groups include,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

The term “cycloalkenyl,” as used herein, means a non-aromatic monocyclicor multicyclic ring system containing at least one carbon-carbon doublebond and preferably having from 5-10 carbon atoms per ring. Exemplarymonocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, andcycloheptenyl.

The term “cycloalkynyl,” as used herein, means a monocyclic ormulticyclic ring system containing at least one carbon-carbon triplebond and preferably having from 5-10 carbon atoms per ring or more than10 carbon atoms per ring.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by a halogen. Representative examples ofhaloalkyl include, but are not limited to, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,and trifluoropropyl such as 3,3,3-trifluoropropyl.

The term “halogen” or “halo” as used herein, means Cl, Br, I, or F.

The term “heteroalkyl” as used herein, means an alkyl group, as definedherein, in which at least one of the carbons of the alkyl group isreplaced with a heteroatom, such as oxygen, nitrogen, and sulfur.Representative examples of heteroalkyls include, but are not limited to,alkyl ethers, secondary and tertiary alkyl amines, amides, and alkylsulfides.

The term “heteroaryl” as used herein, refers to an aromatic monocyclicring or an aromatic bicyclic ring system containing at least oneheteroatom independently selected from the group consisting of N, O, andS. The aromatic monocyclic rings are five or six membered ringscontaining at least one heteroatom independently selected from the groupconsisting of N, O, and S. The five membered aromatic monocyclic ringshave two double bonds and the six membered six membered aromaticmonocyclic rings have three double bonds. The bicyclic heteroaryl groupsare exemplified by a monocyclic heteroaryl ring appended to the parentmolecular moiety and fused to a monocyclic cycloalkyl group, as definedherein, a monocyclic aryl group, as defined herein, a monocyclicheteroaryl group, as defined herein, or a monocyclic heterocycle, asdefined herein. Representative examples of heteroaryl include, but arenot limited to, indolyl, pyridinyl (including pyridin-2-yl,pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl,pyrazolyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl,benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl,benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl,isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl, quinazolinyl,1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, naphthyridinyl,pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl,thiazolo[5,4-d]pyrimidin-2-yl.

The term “heterocycle” or “heterocyclic” or “heterocyclyl” as usedherein means a monocyclic heterocycle, a bicyclic heterocycle(heterobicyclic), or a tricyclic heterocycle. The monocyclic heterocycleis a three-, four-, five-, six-, seven-, or eight-membered ringcontaining at least one heteroatom independently selected from the groupconsisting of 0, N, and S. The three- or four-membered ring containszero or one double bond, and one heteroatom selected from the groupconsisting of 0, N, and S. The five-membered ring contains zero or onedouble bond and one, two, or three heteroatoms selected from the groupconsisting of 0, N, and S. The six-membered ring contains zero, one, ortwo double bonds and one, two, or three heteroatoms selected from thegroup consisting of 0, N, and S. The seven- and eight-membered ringscontains zero, one, two, or three double bonds and one, two, or threeheteroatoms selected from the group consisting of 0, N, and S.Representative examples of monocyclic heterocycles include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle, or a bridged monocyclicheterocycle ring system in which two non-adjacent atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or analkenylene bridge of two, three, or four carbon atoms. Representativeexamples of bicyclic heterocycles include, but are not limited to,benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non-adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heteroarylalkyl” as used herein, refers to a heteroaryl group,as defined herein, appended to the parent molecular moiety through analkylene group, as defined herein.

The term “heterocyclylalkyl” as used herein, refers to a heterocyclegroup, as defined herein, appended to the parent molecular moietythrough an alkylene group, as defined herein.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one —OH group, isappended to the parent molecular moiety through an alkylene group, asdefined herein.

The term “nitro” means a —NO₂ group.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent (e.g., alkyl or cycloalkyl) is indicated by the prefix“C_(x)-C_(y)-”, wherein x is the minimum and y is the maximum number ofcarbon atoms in the substituent. Thus, for example, “C₁-C₃ alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.

The term “substituted” refers to a group that may be further substitutedwith one or more non-hydrogen substituent groups. Substituent groupsinclude, but are not limited to, halogen, ═O (oxo), ═S (thioxo), cyano,nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl,alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl,arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene,aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate,and acyl.

For compounds described herein, groups and substituents thereof may beselected in accordance with permitted valence of the atoms and thesubstituents, such that the selections and substitutions result in astable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

“Amino acid” as used herein refers to naturally occurring andnon-natural synthetic amino acids, as well as amino acid analogs andamino acid mimetics that function in a manner similar to the naturallyoccurring amino acids. Naturally occurring amino acids are those encodedby the genetic code. Amino acids can be referred to herein by eithertheir commonly known three-letter symbols or by the one-letter symbolsrecommended by the IUPAC-IUB Biochemical Nomenclature Commission. Aminoacids include the side chain and polypeptide backbone portions.

The term “antagonist” or “inhibitor” refers to a molecule which blocks(e.g., reduces or prevents) a biological activity. An antagonist orinhibitor inhibits the effect of an agonist. An antagonist may be acompound that inhibits or reduces an activity of a polypeptide. Anantagonist may indirectly or directly bind a polypeptide and inhibit theactivity of the polypeptide, including binding activity or catalyticactivity. For example, an antagonist may prevent expression of apolypeptide, or inhibit the ability of a polypeptide to mediate thebinding of the polypeptide to a ligand. An “allosteric antagonist”refers to a compound that binds to a polypeptide at a secondary site,distinct from the primary ligand binding site, and inhibits or reducesan activity of the polypeptide. The terms “inhibit” or “inhibiting” meanthat an activity is decreased or prevented in the presence of aninhibitor as opposed to in the absence of the inhibitor. The term“inhibition” refers to the reduction or down regulation of a process orthe elimination of a stimulus for a process, which results in theabsence or minimization of the expression or activity of a biomoleculeor polypeptide. Inhibition may be direct or indirect. Inhibition may bespecific, that is, the inhibitor inhibits a biomolecule or polypeptideand not others.

As used herein, the term “agonist” refers to a biologically activeligand that binds to its complementary biologically active receptor andactivates the receptor either to cause a biological response in thereceptor or to enhance a biological activity of the receptor. An agonistmay be a molecule or compound that triggers (e.g., initiates orpromotes), partially or fully enhances, stimulates, or activates one ormore biological activities. An agonist may mimic the action of anaturally occurring substance. Whereas an agonist causes an action, anantagonist blocks the action of the agonist.

The terms “control,” “reference level,” and “reference” are used hereininterchangeably. The reference level may be a predetermined value orrange, which is employed as a benchmark against which to assess themeasured result. “Control group” as used herein refers to a group ofcontrol subjects. The predetermined level may be a cutoff value from acontrol group. The predetermined level may be an average from a controlgroup. Cutoff values (or predetermined cutoff values) may be determinedby Adaptive Index Model (AIM) methodology. Cutoff values (orpredetermined cutoff values) may be determined by a receiver operatingcurve (ROC) analysis from biological samples of the patient group. ROCanalysis, as generally known in the biological arts, is a determinationof the ability of a test to discriminate one condition from another,e.g., to determine the performance of each marker in identifying apatient having CRC. A description of ROC analysis is provided in P. J.Heagerty et al. (Biometrics 2000, 56, 337-44), the disclosure of whichis hereby incorporated by reference in its entirety. Alternatively,cutoff values may be determined by a quartile analysis of biologicalsamples of a patient group. For example, a cutoff value may bedetermined by selecting a value that corresponds to any value in the25th-75th percentile range, preferably a value that corresponds to the25th percentile, the 50th percentile or the 75th percentile, and morepreferably the 75th percentile. Such statistical analyses may beperformed using any method known in the art and can be implementedthrough any number of commercially available software packages (e.g.,from Analyse-it Software Ltd., Leeds, UK; StataCorp LP, College Station,Tex.; SAS Institute Inc., Cary, N.C.). The healthy or normal levels orranges for a target or for a protein activity may be defined inaccordance with standard practice. A control may be a subject or cellwithout a compound as detailed herein. A control may be a subject, or asample therefrom, whose disease state is known. The subject, or sampletherefrom, may be healthy, diseased, diseased prior to treatment,diseased during treatment, or diseased after treatment, or a combinationthereof. The term “normal subject” as used herein means a healthysubject, i.e., a subject having no clinical signs or symptoms ofdisease. The normal subject may be clinically evaluated for otherwiseundetected signs or symptoms of disease, which evaluation may includeroutine physical examination and/or laboratory testing. In someembodiments, the control is a healthy control. In some embodiments, thecontrol comprises neurodegenerative disease.

“Neurodegenerative Diseases” are disorders characterized by, resultingfrom, or resulting in the progressive loss of structure or function ofneurons, including death of neurons. Neurodegeneration can be found inmany different levels of neuronal circuitry ranging from molecular tosystemic. Some neurodegenerative diseases are caused by geneticmutations. Some neurodegenerative diseases are classified asproteopathies because they are associated with the aggregation ofmisfolded proteins. Neurodegenerative diseases include, for example,Alzheimer's Disease (AD), amyotrophic lateral sclerosis (ALS),Parkinson's Disease (PD), Huntington's Disease, prion disease, motorneuron disease, spinocerebellar ataxia, spinal muscular atrophy,neuronal loss, cognitive defect, primary age-related tauopathy(PART)/Neurofibrillary tangle-predominant senile dementia, chronictraumatic encephalopathy including dementia pugilistica, dementia withLewy bodies, neuroaxonal dystrophies, and multiple system atrophy,progressive supranuclear palsy, Pick's Disease, corticobasaldegeneration, some forms of frontotemporal lobar degeneration,frontotemporal dementia and parkinsonism linked to chromosome 17,Lytico-Bodig disease (Parkinson-dementia complex of Guam),ganglioglioma, gangliocytoma, meningioangiomatosis, postencephaliticparkinsonism, subacute sclerosing panencephalitis, lead encephalopathy,tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

“Polynucleotide” as used herein can be single stranded or doublestranded, or can contain portions of both double stranded and singlestranded sequence. The polynucleotide can be nucleic acid, natural orsynthetic, DNA, genomic DNA, cDNA, RNA, or a hybrid, where thepolynucleotide can contain combinations of deoxyribo- andribo-nucleotides, and combinations of bases including, for example,uracil, adenine, thymine, cytosine, guanine, inosine, xanthinehypoxanthine, isocytosine, and isoguanine. Polynucleotides can beobtained by chemical synthesis methods or by recombinant methods.

A “peptide” or “polypeptide” is a linked sequence of two or more aminoacids linked by peptide bonds. The polypeptide can be natural,synthetic, or a modification or combination of natural and synthetic.Peptides and polypeptides include proteins such as binding proteins,receptors, and antibodies. The terms “polypeptide”, “protein,” and“peptide” are used interchangeably herein. “Primary structure” refers tothe amino acid sequence of a particular peptide. “Secondary structure”refers to locally ordered, three dimensional structures within apolypeptide such as beta-sheet and alpha-helix. These can formstructures commonly known as domains, e.g., enzymatic domains,extracellular domains, transmembrane domains, pore domains, andcytoplasmic tail domains. “Domains” are portions of a polypeptide thatform a compact unit of the polypeptide and are typically 15 to 350 aminoacids long. Exemplary domains include domains with enzymatic activity orligand binding activity. Typical domains are made up of sections oflesser organization such as stretches of beta-sheet and alpha-helices.“Tertiary structure” refers to the complete three dimensional structureof a polypeptide monomer. “Quaternary structure” refers to the threedimensional structure formed by the noncovalent association ofindependent tertiary units. A “motif” is a portion of a polypeptidesequence and includes at least two amino acids. A motif may be 2 to 20,2 to 15, or 2 to 10 amino acids in length. In some embodiments, a motifincludes 3, 4, 5, 6, or 7 sequential amino acids. A domain may becomprised of a series of the same type of motif.

A “pharmaceutically acceptable excipient,” “pharmaceutically acceptablediluent,” “pharmaceutically acceptable carrier,” or “pharmaceuticallyacceptable adjuvant” as used interchangeably herein means an excipient,diluent, carrier, and/or adjuvant that is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable, and includes anexcipient, diluent, carrier, and adjuvant that is acceptable forveterinary use and/or human pharmaceutical use, such as thosepromulgated by the United States Food and Drug Administration.

“Recombinant” when used with reference, e.g., to a cell, or nucleicacid, protein, or vector, indicates that the cell, nucleic acid,protein, or vector, has been modified by the introduction of aheterologous nucleic acid or protein or the alteration of a nativenucleic acid or protein, or that the cell is derived from a cell somodified. Thus, for example, recombinant cells express genes that arenot found within the native (non-recombinant) form of the cell orexpress native genes that are otherwise abnormally expressed, underexpressed, or not expressed at all.

“Sample” or “test sample” as used herein can mean any sample in whichthe presence and/or level of a target or activity is to be detected ordetermined or any sample comprising a compound or composition asdetailed herein. Samples may include liquids, solutions, emulsions, orsuspensions. Samples may include a medical sample. Samples may includeany biological fluid or tissue, such as blood, whole blood, fractions ofblood such as plasma and serum, muscle, interstitial fluid, sweat,saliva, urine, tears, synovial fluid, bone marrow, cerebrospinal fluid,nasal secretions, sputum, amniotic fluid, bronchoalveolar lavage fluid,gastric lavage, emesis, fecal matter, lung tissue, peripheral bloodmononuclear cells, total white blood cells, lymph node cells, spleencells, tonsil cells, cancer cells, tumor cells, bile, digestive fluid,skin, or combinations thereof. In some embodiments, the sample comprisesan aliquot. In other embodiments, the sample comprises a biologicalfluid. Samples can be obtained by any means known in the art. The samplecan be used directly as obtained from a patient or can be pre-treated,such as by filtration, distillation, extraction, concentration,centrifugation, inactivation of interfering components, addition ofreagents, and the like, to modify the character of the sample in somemanner as discussed herein or otherwise as is known in the art. Samplesmay be obtained before diagnosis, before treatment, during treatment,after treatment, or after diagnosis, or a combination thereof.

“Subject” as used herein can mean a mammal that wants or is in need ofthe herein described compounds. The subject may be a patient. Thesubject may be a human or a non-human animal. The subject may be avertebrate. The subject may be a mammal. The mammal may be a primate ora non-primate. The mammal can be a primate such as a human; anon-primate such as, for example, dog, cat, horse, cow, pig, mouse, rat,camel, llama, goat, rabbit, sheep, hamster, and guinea pig; or non-humanprimate such as, for example, monkey, chimpanzee, gorilla, orangutan,and gibbon. The subject may be male. The subject may be female. Thesubject may be of any age or stage of development, such as, for example,an adult, an adolescent, a child, or an infant. In some embodiments, thesubject is human. In some embodiments, the subject has a specificgenetic marker. In some embodiments, the subject may be diagnosed withor at risk of developing a neurodegenerative disease. The subject orpatient may be undergoing other forms of treatment.

“Substantially identical” can mean that a first and second amino acid orpolynucleotide sequence are at least 60%, 65%, 70%, 75%, 80%, 85%, 90%,95%, 96%, 97%, 98%, or 99% over a region of 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 1100 amino acids or nucleotides.

“Target” as used herein can refer to an entity that a drug moleculebinds. A target may include, for example, a small molecule, a protein, apolypeptide, a polynucleotide, a carbohydrate, or a combination thereof.

A “therapeutically effective amount” is an amount sufficient to elicit atherapeutic effect. Amounts effective for this use will depend on, e.g.,the particular composition of the regimen administered, the manner ofadministration, the stage and severity of the disease, the general stateof health of the subject, and the judgment of the prescribing physician.A therapeutically effective amount is also one in which any toxic ordetrimental effects of substance are outweighed by the therapeuticallybeneficial effects. A “prophylactically effective amount” refers to anamount effective, at dosages and for periods of time necessary, toachieve the desired prophylactic result. Typically, since a prophylacticdose is used in subjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

A therapeutically effective amount may be administered in one or moreadministrations (e.g., the composition may be given as a preventativetreatment or therapeutically at any stage of disease progression, beforeor after symptoms, and the like), applications or dosages and is notintended to be limited to a particular formulation, combination oradministration route. It is within the scope of the present disclosurethat the disclosed compositions may be administered at various timesduring the course of treatment of the subject. The times ofadministration and dosages used will depend on several factors, such asthe goal of treatment (e.g., treating v. preventing), condition of thesubject, etc. and can be readily determined by one skilled in the art.Administration may be adjusted according to individual need andprofessional judgment of a person administrating or supervising theadministration of the compounds used in the present invention.

“Toxic” refers to a substance causing any adverse effect whenadministered to a subject. The term “non-toxic” refers to a substancethat has a relatively low degree to which it can damage a subject.Toxicity can refer to the effect on a whole organism, such as an animal,bacterium, plant, or other subject as defined herein, as well as theeffect on a substructure of the organism, such as a cell (cytotoxicity)or an organ (organotoxicity), such as the liver (hepatotoxicity). Acentral concept of toxicology is that effects are dose-dependent; evenwater can lead to water intoxication when taken in large enough doses,whereas for even a very toxic substance such as snake venom there is adose below which there is no detectable toxic effect. A composition orcompound that is relatively non-toxic may allow a wider range ofsubjects to be able to safely handle the composition or compound,without serious safety concerns or risks.

The terms “treat,” “treated,” or “treating” as used herein refers to atherapeutic wherein the object is to slow down (lessen) an undesiredphysiological condition, disorder or disease, or to obtain beneficial ordesired clinical results. For the purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment alsoincludes prolonging survival as compared to expected survival if notreceiving treatment. “Treat,” “treatment,” or “treating,” when referringto protection of a subject from a disease or infection meanssuppressing, repressing, ameliorating, or completely eliminating thedisease or infection. Preventing the disease or infection involvesadministering a compound or composition of the present invention to asubject prior to onset of the disease or infection. Suppressing thedisease or infection involves administering a compound or composition ofthe present invention to a subject after induction of the disease orinfection but before its clinical appearance. Repressing or amelioratingthe disease or infection involves administering a compound orcomposition of the present invention to a subject after clinicalappearance of the disease or infection.

“Variant” as used herein with respect to a polynucleotide means (i) aportion or fragment of a referenced nucleotide sequence; (ii) thecomplement of a referenced nucleotide sequence or portion thereof; (iii)a polynucleotide that is substantially identical to a referencedpolynucleotide or the complement thereof; or (iv) a polynucleotide thathybridizes under stringent conditions to the referenced polynucleotide,complement thereof, or a sequence substantially identical thereto.

A “variant” can further be defined as a peptide or polypeptide thatdiffers in amino acid sequence by the insertion, deletion, orconservative substitution of amino acids, but retain at least onebiological activity. Representative examples of “biological activity”include the ability to be bound by a specific antibody or polypeptide orto promote an immune response. Variant can mean a substantiallyidentical sequence. Variant can mean a functional fragment thereof.Variant can also mean multiple copies of a polypeptide. The multiplecopies can be in tandem or separated by a linker. Variant can also meana polypeptide with an amino acid sequence that is substantiallyidentical to a referenced polypeptide with an amino acid sequence thatretains at least one biological activity. A conservative substitution ofan amino acid, i.e., replacing an amino acid with a different amino acidof similar properties (e.g., hydrophilicity, degree and distribution ofcharged regions) is recognized in the art as typically involving a minorchange. These minor changes can be identified, in part, by consideringthe hydropathic index of amino acids. See Kyte et al., J. Mol. Biol.1982, 157, 105-132. The hydropathic index of an amino acid is based on aconsideration of its hydrophobicity and charge. It is known in the artthat amino acids of similar hydropathic indexes can be substituted andstill retain protein function. In one aspect, amino acids havinghydropathic indices of ±2 are substituted. The hydrophobicity of aminoacids can also be used to reveal substitutions that would result inpolypeptides retaining biological function. A consideration of thehydrophilicity of amino acids in the context of a polypeptide permitscalculation of the greatest local average hydrophilicity of thatpolypeptide, a useful measure that has been reported to correlate wellwith antigenicity and immunogenicity, as discussed in U.S. Pat. No.4,554,101, which is fully incorporated herein by reference. Substitutionof amino acids having similar hydrophilicity values can result inpolypeptides retaining biological activity, for example immunogenicity,as is understood in the art. Substitutions can be performed with aminoacids having hydrophilicity values within ±2 of each other. Both thehydrophobicity index and the hydrophilicity value of amino acids areinfluenced by the particular side chain of that amino acid. Consistentwith that observation, amino acid substitutions that are compatible withbiological function are understood to depend on the relative similarityof the amino acids, and particularly the side chains of those aminoacids, as revealed by the hydrophobicity, hydrophilicity, charge, size,and other properties.

A variant can be a polynucleotide sequence that is substantiallyidentical over the full length of the full gene sequence or a fragmentthereof. The polynucleotide sequence can be 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, or 100% identical over the full length of the gene sequence or afragment thereof. A variant can be an amino acid sequence that issubstantially identical over the full length of the amino acid sequenceor fragment thereof. The amino acid sequence can be 80%, 81%, 82%, 83%,84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, or 100% identical over the full length of the amino acidsequence or a fragment thereof.

2. COMPOUNDS

Provided herein is a compound, such as the following:

or a pharmaceutically acceptable salt thereof. The compound shown abovemay be referred to as “HW-C-9.”

The compound may be described as a γ-AApeptide. γ-AApeptides are a classof non-natural peptides. Non-natural peptides may also be referred to aspeptidomimetics and may further include peptoids, β-peptides, andN-acylated polyamine. Natural peptides include α-peptides. γ-AApeptidesinclude N-acylated-N-aminoethyl amino acid units derived from γ-PNAs(FIG. 1). Each unit (building block) of a γ-AApeptide is comparable to adipeptide residue in a natural peptide. As such, γ-AApeptides mayproject an identical number of functional groups as natural peptides ofthe same length. Half of the side chains of γ-AApeptides may be chiral.γ-AApeptides may be resistant to proteolytic degradation.

The compound, or a pharmaceutically acceptable salt thereof, may existas a stereoisomer wherein asymmetric or chiral centers are present. Thestereoisomer is “R” or “S” depending on the configuration ofsubstituents around the chiral carbon atom. The terms “R” and “S” usedherein are configurations as defined in IUPAC 1974 Recommendations forSection E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45,13-30. The disclosure contemplates various stereoisomers and mixturesthereof and these are specifically included within the scope of thisinvention. Stereoisomers include enantiomers and diastereomers, andmixtures of enantiomers or diastereomers. Individual stereoisomers ofthe compounds may be prepared synthetically from commercially availablestarting materials, which contain asymmetric or chiral centers or bypreparation of racemic mixtures followed by methods of resolutionwell-known to those of ordinary skill in the art. These methods ofresolution are exemplified by (1) attachment of a mixture of enantiomersto a chiral auxiliary, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography and optionalliberation of the optically pure product from the auxiliary as describedin Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook ofPractical Organic Chemistry,” 5th edition (1989), Longman Scientific &Technical, Essex CM20 2JE, England, or (2) direct separation of themixture of optical enantiomers on chiral chromatographic columns, or (3)fractional recrystallization methods.

It should be understood that the compound may possess tautomeric forms,as well as geometric isomers, and that these also constitute embodimentsof the disclosure.

The present disclosure also includes an isotopically-labeled compound,which is identical to the compound shown above, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes suitable for inclusion in the compounds ofthe invention are hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, and chlorine, such as, but not limited to ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Substitution with heavier isotopes such as deuterium, i.e. ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances. Thecompound may incorporate positron-emitting isotopes for medical imagingand positron-emitting tomography (PET) studies for determining thedistribution of receptors. Suitable positron-emitting isotopes that canbe incorporated in the compound are ¹¹C, ¹³N, ¹⁵O, and ¹⁸F.Isotopically-labeled compounds can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples using appropriateisotopically-labeled reagent in place of non-isotopically-labeledreagent.

a. Pharmaceutically Acceptable Salts

The disclosed compounds may exist as pharmaceutically acceptable salts.The term “pharmaceutically acceptable salt” refers to salts orzwitterions of the compounds which are water or oil-soluble ordispersible, suitable for treatment of disorders without undue toxicity,irritation, and allergic response, commensurate with a reasonablebenefit/risk ratio and effective for their intended use. The salts maybe prepared during the final isolation and purification of the compoundsor separately by reacting an amino group of the compounds with asuitable acid. For example, a compound may be dissolved in a suitablesolvent, such as but not limited to methanol and water and treated withat least one equivalent of an acid, like hydrochloric acid. Theresulting salt may precipitate out and be isolated by filtration anddried under reduced pressure. Alternatively, the solvent and excess acidmay be removed under reduced pressure to provide a salt. Representativesalts include acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, isethionate, fumarate, lactate, maleate, methanesulfonate,naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,glutamate, para-toluenesulfonate, undecanoate, hydrochloric,hydrobromic, sulfuric, phosphoric, and the like. The amino groups of thecompounds may also be quaternized with alkyl chlorides, bromides andiodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl,myristyl, stearyl, and the like.

Basic addition salts may be prepared during the final isolation andpurification of the disclosed compounds by reaction of a carboxyl groupwith a suitable base such as the hydroxide, carbonate, or bicarbonate ofa metal cation such as lithium, sodium, potassium, calcium, magnesium,or aluminum, or an organic primary, secondary, or tertiary amine.Quaternary amine salts can be prepared, such as those derived frommethylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine,dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine andN,N′-dibenzylethylenediamine, ethylenediamine, ethanolamine,diethanolamine, piperidine, piperazine, and the like.

b. Synthesis of Compounds

The compounds may be made on a solid phase using the protocol publishedpreviously (Wu, Haifan et al. γ-AApeptide-based small-molecule ligandsthat inhibit Aβ aggregation. Chem. Commun. 2014, 50, 5206-5208,incorporated herein by reference) and as detailed in Example 1 and FIG.2. Alternatively, the compounds as detailed herein may be syntheticallymade by methods known to one of skill in the art. The compounds may bepurified by methods known to one of skill in the art, such as, forexample, chromatography such as HPLC. The structure and sequence of thecompounds may be confirmed by methods known to one of skill in the art,such as, for example, mass spectrometry.

c. Pharmaceutical Compositions

The compounds or salts thereof as detailed herein may be formulated intopharmaceutical compositions accordance with standard techniques wellknown to those skilled in the pharmaceutical art.

The composition may comprise the compound or salt thereof and apharmaceutically acceptable carrier. The term “pharmaceuticallyacceptable carrier,” as used herein, means a non-toxic, inert solid,semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type.

The route by which the disclosed compounds or salts thereof areadministered and the form of the composition will dictate the type ofcarrier to be used. The pharmaceutical composition may be in a varietyof forms, suitable, for example, for systemic administration (e.g.,oral, rectal, sublingual, buccal, implants, intranasal, intravaginal,transdermal, intravenous, intraarterial, intratumoral, intraperitoneal,or parenteral) or topical administration (e.g., dermal, pulmonary,nasal, aural, ocular, liposome delivery systems, or iontophoresis).Parenteral administration may include subcutaneous, intravenous,intramuscular, intrathecal, or intrasternal injection, or infusiontechniques. Injectable preparations, for example, sterile injectableaqueous or oleaginous suspensions, may be formulated according to theknown art using suitable pharmaceutically acceptable carriers. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic pharmaceutically acceptable carrier. Amongthe acceptable carriers that may be employed are water, Ringer'ssolution, isotonic sodium chloride solution. In addition, sterile, fixedoils may be used as a carrier. For this purpose, any bland fixed oil maybe employed, including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid may be used. Other suitablepharmaceutically acceptable carriers may include dimethyl acetamide,surfactants including ionic and non-ionic detergents, and polyethyleneglycols. The disclosed compositions may be sterile and stable under theconditions of manufacture and storage. For this purpose, suitablepreservatives may be used in the disclosed compositions. For example,the disclosed compositions may comprise benzalkonium chloride, methylparaben and/or sodium benzoate. The amount of preservative(s) in acomposition is typically about 0.01 to about 5%. Suitable pH adjustingadditives may also be added to the pharmaceutical composition. SuitablepH adjusting additives may include HCl or NaOH in amounts sufficient toadjust the pH of the pharmaceutical composition. Mixtures ofpharmaceutically acceptable carriers such as those disclosed herein mayalso be used. In some embodiments, the pharmaceutical composition is foradministration to a subject's central nervous system. Techniques andformulations may generally be found in “Remington's PharmaceuticalSciences,” (Meade Publishing Co., Easton, Pa.). Pharmaceuticalcompositions must typically be sterile and stable under the conditionsof manufacture and storage. All carriers are optional in thecompositions.

Pharmaceutically acceptable carriers include, for example, diluents,lubricants, binders, disintegrants, colorants, flavors, sweeteners,antioxidants, preservatives, glidants, solvents, suspending agents,wetting agents, surfactants, emollients, propellants, humectants,powders, pH adjusting agents, and combinations thereof.

Suitable diluents include, for example, sugars such as glucose, lactose,dextrose, and sucrose; diols such as propylene glycol; calciumcarbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol;sorbitol; cellulose; starch; and gelatin. The amount of diluent(s) in asystemic or topical composition may typically be about 50 to about 90%.

Suitable lubricants include, for example, silica, talc, stearic acid andits magnesium salts and calcium salts, calcium sulfate; and liquidlubricants such as polyethylene glycol and vegetable oils such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil, and oil oftheobroma. The amount of lubricant(s) in a systemic or topicalcomposition may typically be about 5 to about 10%.

Suitable binders include, for example, polyvinyl pyrrolidone; magnesiumaluminum silicate; starches such as corn starch and potato starch;gelatin; tragacanth; sucrose; and cellulose and its derivatives, such assodium carboxymethylcellulose, ethyl cellulose, methylcellulose,microcrystalline cellulose, and hydroxypropyl methylcellulose. Theamount of binder(s) in a systemic composition may typically be about 5to about 50%.

Suitable disintegrants include, for example, agar, alginic acid and thesodium salt thereof, effervescent mixtures, croscarmelose, crospovidone,sodium carboxymethyl starch, sodium starch glycolate, clays, and ionexchange resins. The amount of disintegrant(s) in a systemic or topicalcomposition may typically be about 0.1 to about 10%.

Suitable colorants include, for example, a colorant such as an FD&C dye.When used, the amount of colorant in a systemic or topical compositionmay typically be about 0.005 to about 0.1%.

Suitable flavors include, for example, menthol, peppermint, and fruitflavors. The amount of flavor(s), when used, in a systemic or topicalcomposition may typically be about 0.1 to about 1.0%.

Suitable sweeteners include, for example, aspartame and saccharin, or acombination thereof. The amount of sweetener(s) in a systemic or topicalcomposition may typically be about 0.001 to about 1%.

Suitable antioxidants include, for example, butylated hydroxyanisole(“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount ofantioxidant(s) in a systemic or topical composition may typically beabout 0.1 to about 5%.

Suitable preservatives include, for example, benzalkonium chloride,methyl paraben, and sodium benzoate. The amount of preservative(s) in asystemic or topical composition may typically be about 0.01 to about 5%.

Suitable glidants include, for example, silicon dioxide. The amount ofglidant(s) in a systemic or topical composition may typically be about 1to about 5%.

Suitable solvents include, for example, water, isotonic saline, ethyloleate, glycerine, castor oils, hydroxylated castor oils, alcohols suchas ethanol or isopropanol, methylene chloride, ethylene glycol monoethylether, diethylene glycol monobutyl ether, diethylene glycol monoethylether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, andphosphate buffer solutions, and combinations thereof. The amount ofsolvent(s) in a systemic or topical composition is typically from about0 to about 100%, or 0% to about 95%.

Suitable suspending agents include, for example, AVICEL RC-591 (from FMCCorporation of Philadelphia, Pa.) and sodium alginate. The amount ofsuspending agent(s) in a systemic or topical composition may typicallybe about 1 to about 8%.

Suitable surfactants include, for example, lecithin, Polysorbate 80, andsodium lauryl sulfate, and the TWEENS from Atlas Powder Company ofWilmington, Del. Suitable surfactants include those disclosed in theC.T.F.A. Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington'sPharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon'sVolume 1, Emulsifiers & Detergents, 1994, North American Edition, pp.236-239. The amount of surfactant(s) in the systemic or topicalcomposition may typically be about 0.1% to about 5%.

Suitable emollients include, for example, stearyl alcohol, glycerylmonoricinoleate, glyceryl monostearate, propane-1,2-diol,butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearicacid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyllaurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol,cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropylpalmitate, isopropyl stearate, butyl stearate, polyethylene glycol,triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil,castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butylmyristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryllactate, myristyl lactate, decyl oleate, myristyl myristate, andcombinations thereof. Specific emollients for skin include stearylalcohol and polydimethylsiloxane. The amount of emollient(s) in askin-based topical composition may typically be about 5% to about 95%.

Suitable propellants include, for example, propane, butane, isobutane,dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.The amount of propellant in a topical composition may be about 0% toabout 95%.

Suitable humectants include, for example, glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,gelatin, and combinations thereof. The amount of humectant in a topicalcomposition may be about 0% to about 95%.

Suitable powders include, for example, beta-cyclodextrins, hydroxypropylcyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums,colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammoniumsmectites, trialkyl aryl ammonium smectites, chemically-modifiedmagnesium aluminum silicate, organically-modified Montmorillonite clay,hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodiumcarboxymethyl cellulose, ethylene glycol monostearate, and combinationsthereof. The amount of powder(s) in a topical composition may typicallybe 0% to 95%.

Suitable pH adjusting additives include, for example, HCl or NaOH inamounts sufficient to adjust the pH of a topical pharmaceuticalcomposition.

In some embodiments, the pharmaceutically acceptable carrier is a sugarsuch as lactose, glucose, and sucrose. In some embodiments, thepharmaceutically acceptable carrier is a starch such as, for example,corn starch and potato starch. In some embodiments, the pharmaceuticallyacceptable carrier is cellulose and its derivatives such as, but notlimited to, sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate. In some embodiments, the pharmaceutically acceptablecarrier is powdered tragacanth, malt, gelatin, or talc. In someembodiments, the pharmaceutically acceptable carrier is an excipientsuch as, but not limited to, cocoa butter and suppository waxes. In someembodiments, the pharmaceutically acceptable carrier is oil such as, butnot limited to, peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil. In some embodiments, thepharmaceutically acceptable carrier is a glycol, such as propyleneglycol. In some embodiments, the pharmaceutically acceptable carrier isan ester such as, but not limited to, ethyl oleate and ethyl laurate. Insome embodiments, the pharmaceutically acceptable carrier is an agar. Insome embodiments, the pharmaceutically acceptable carrier is a bufferingagent such as, but not limited to, magnesium hydroxide and aluminumhydroxide. In some embodiments, the pharmaceutically acceptable carrieris alginic acid, pyrogen-free water, isotonic saline, Ringer's solution,ethyl alcohol, or a phosphate buffer solution. In some embodiments, thepharmaceutically acceptable carrier is a non-toxic compatible lubricantsuch as, but not limited to, sodium lauryl sulfate and magnesiumstearate.

Compositions for oral administration can have various dosage forms. Forexample, solid forms include tablets, capsules, granules, and bulkpowders. Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed. Tablets typicallyinclude an active component, and a carrier comprising ingredientsselected from diluents, lubricants, binders, disintegrants, colorants,flavors, sweeteners, glidants, and combinations thereof. Capsules(including implants, time release, and sustained release formulations)typically include a compound or salt thereof, and a carrier includingone or more diluents disclosed above in a capsule comprising gelatin.Granules typically comprise a compound or salt thereof, and preferablyglidants such as silicon dioxide to improve flow characteristics.Implants can be of the biodegradable or the non-biodegradable type.

Compositions for oral administration can have solid forms. Solid oralcompositions may be coated by conventional methods, typically with pH ortime-dependent coatings, such that a compound is released in thegastrointestinal tract in the vicinity of the desired application, or atvarious points and times to extend the desired action. The coatingstypically include one or more components selected from the groupconsisting of cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT®coatings (available from Evonik Industries of Essen, Germany), waxes,and shellac.

Compositions for oral administration can have liquid forms. For example,suitable liquid forms include aqueous solutions, emulsions, suspensions,solutions reconstituted from non-effervescent granules, suspensionsreconstituted from non-effervescent granules, effervescent preparationsreconstituted from effervescent granules, elixirs, tinctures, syrups,and the like. Liquid orally administered compositions typically includea compound or salt thereof and a carrier, namely, a carrier selectedfrom diluents, colorants, flavors, sweeteners, preservatives, solvents,suspending agents, and surfactants. Peroral liquid compositionspreferably include one or more ingredients selected from colorants,flavors, and sweeteners.

Compositions for topical administration can be applied locally to theskin and may be in any form including solids, solutions, oils, creams,ointments, gels, lotions, shampoos, leave-on and rinse-out hairconditioners, milks, cleansers, moisturizers, sprays, skin patches, andthe like. The carrier of the topical composition preferably aidspenetration of the compound into the skin. In the topical compositions,the carrier includes a topical carrier. Suitable topical carriers caninclude one or more ingredients selected from phosphate buffered saline,isotonic water, deionized water, monofunctional alcohols, symmetricalalcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethylisosorbide, castor oil, combinations thereof, and the like. Moreparticularly, carriers for skin applications may include propyleneglycol, dimethyl isosorbide, and water, and even more particularly,phosphate buffered saline, isotonic water, deionized water,monofunctional alcohols, and symmetrical alcohols. The carrier of atopical composition may further include one or more ingredients selectedfrom emollients, propellants, solvents, humectants, thickeners, powders,fragrances, pigments, and preservatives, all of which are optional.

Although the amounts of components in the compositions may varydepending on the type of composition prepared, in general, systemiccompositions may include 0.01% to 50% of a compound and 50% to 99.99% ofone or more carriers. Compositions for parenteral administration maytypically include 0.1% to 10% of a compound and 90% to 99.9% of one ormore carriers. Oral dosage forms may include, for example, at leastabout 5%, or about 25% to about 50% of a compound. The oral dosagecompositions may include about 50% to about 95% of carriers, or fromabout 50% to about 75% of carriers. The amount of the carrier employedin conjunction with a disclosed compound or salt thereof is sufficientto provide a practical quantity of composition for administration perunit dose of the compound. Techniques and compositions for making dosageforms useful in the methods of this invention are described in thefollowing references: Modern Pharmaceutics, Chapters 9 and 10, Banker &Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms:Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms,2nd Ed., (1976).

d. Administration

The compounds or salts thereof as detailed herein, or the pharmaceuticalcompositions comprising the same, may be administered to a subject. Theterm “administration” or “administering,” as used herein, refers toproviding, contacting, and/or delivery of a compound or salt orcomposition by any appropriate route to achieve the desired effect. Suchcompositions comprising a compound or salt thereof can be administeredin dosages and by techniques well known to those skilled in the medicalarts taking into consideration such factors as the age, sex, weight, andcon dition of the particular subject, and the route of administration.

The compound or salt thereof can be administered prophylactically ortherapeutically. In prophylactic administration, the compound or saltthereof can be administered in an amount sufficient to induce aresponse. In therapeutic applications, the compounds or salts thereofare administered to a subject in need thereof in an amount sufficient toelicit a therapeutic effect. The compound or salt thereof may beadministered in a therapeutically effective amount.

The pharmaceutical compositions may include a therapeutically effectiveamount of the compound or salt thereof. Any suitable therapeuticallyeffective amount of the compound or salt thereof may be used in thepharmaceutical composition. For example, a therapeutically effectiveamount of a compound or a pharmaceutically acceptable salt thereof, maybe about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about 950 mg/kg,about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about 850 mg/kg,about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about 750 mg/kg,about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about 650 mg/kg,about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about 550 mg/kg,about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about 450 mg/kg,about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about 350 mg/kg,about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about 250 mg/kg,about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about 150 mg/kg,and about 90 mg/kg to about 100 mg/kg.

The compound or salt thereof can be administered by methods well knownin the art as described in Donnelly et al. (Ann. Rev. Immunol. 1997, 15,617-648); Feigner et al. (U.S. Pat. No. 5,580,859, issued Dec. 3, 1996);Feigner (U.S. Pat. No. 5,703,055, issued Dec. 30, 1997); and Carson etal. (U.S. Pat. No. 5,679,647, issued Oct. 21, 1997), the contents of allof which are incorporated herein by reference in their entirety. Thecompound or salt thereof can be complexed to particles or beads that canbe administered to an individual, for example, using a vaccine gun. Oneskilled in the art would know that the choice of a pharmaceuticallyacceptable carrier, including a physiologically acceptable compound,depends, for example, on the route of administration.

The compound or salt thereof can be delivered via a variety of routes.Typical delivery routes include parenteral administration, e.g.,intradermal, intramuscular or subcutaneous delivery. Other routesinclude oral administration, intranasal, intravaginal, transdermal,intravenous, intraarterial, intratumoral, intraperitoneal, and epidermalroutes. In some embodiments, the compound is administered intravenously,intranasally, intraarterially, or intraperitoneally to the subject. Insome embodiments, the compound or salt thereof is administeredintranasally to the subject. In some embodiments, the compound or saltthereof crosses the blood-brain barrier of the subject.

Administration methods are preferably those that are effective tocircumvent the blood-brain barrier and are effective to deliver thedisclosed compounds or compositions to the central nervous system. Forexample, delivery methods may include the use of nanoparticles. Theparticles may be of any suitable structure. Positively charged lipidsare particularly preferred for the formulation of such nanoparticles.The preparation of such lipid particles is well known in the art. See,for example, U.S. Pat. No. 4,880,635 to Janoff et al.; U.S. Pat. No.4,906,477 to Kurono et al.; 4,91 1,928 to Wallach; U.S. Pat. No.4,917,951 to Wallach; U.S. Pat. No. 4,920,016 to Allen et al.; U.S. Pat.No. 4,921,757 to Wheatley et al.; etc.

The disclosed compounds or salts thereof or compositions may beadministered in a bolus directly into the central nervous system. Thecomposition may be administered to the subject in a bolus once, ormultiple times. When administered multiple times, the compositions maybe administered at regular intervals or at intervals that may varyduring the treatment of a subject.

The disclosed compounds or salts thereof or compositions may beadministered by continuous infusion into the central nervous system.Non-limiting examples of methods that may be used to deliver thedisclosed compounds or salts thereof or compositions into the centralnervous system by continuous infusion may include pumps, wafers, gels,foams and fibrin clots. For example, the disclosed compounds or saltsthereof or compositions may be delivered into the central nervous systemby continuous infusion using an osmotic pump.

The disclosed compounds or salts thereof or compositions may beadministered to the patient at any frequency necessary to achieve thedesired therapeutic effect. The disclosed compounds or salts thereof orcompositions may be administered to the subject as a single dose, ormultiple doses over a period of time. For example, the compounds orsalts thereof or compositions may be administered once to several timesevery month, every two weeks, every week, or every day. Administrationof the compounds or salts thereof or compositions may be repeated untilthe desired therapeutic effect has been achieved. For example, thecompounds or salts thereof or compositions may be administered once toseveral times over the course of 1 day, 3 days, 5 days, 1 week, 2 weeks,3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

The disclosed compounds or salts thereof or compositions may beadministered to a subject in combination with other therapies. Forexample, the disclosed compounds or salts thereof or compositions may beadministered to a subject with other therapies to reduce aggregation oftau, synuclein, amyloid beta, or a combination thereof. As anotherexample, the disclosed compounds or salts thereof or compositions may beadministered to a subject in combination with other therapies for thetreatment of a neurodegenerative disease.

3. NEURODEGENERATIVE DISEASES

The compounds or salts thereof as detailed herein may be used to treatneurodegenerative diseases. Neurodegenerative diseases includeproteinopathies.

Proteinopathies are diseases or disorders in which a protein becomesstructurally abnormal. For example, the protein may fail to properlyfold into its normal configuration, e.g., become misfolded. In someembodiments, the proteins form aggregates. Aggregates may includefibrillar aggregates, or fibrils. Protein misfolding may include changesto the secondary and/or tertiary structure of a protein. For example, aprotein may become structurally abnormal by increasing the beta-sheetsecondary structure of the protein. The abnormal structure of theprotein may disrupt its function, such as gaining a new function orlosing normal function. The structurally abnormal protein may therebydisrupt the function of cells, tissues, and/or organs. Proteinopathiesmay also be referred to as proteopathies, protein confirmationdisorders, or protein misfolding diseases. The compounds or saltsthereof as detailed herein may be used to treat proteinopathiesassociated with protein aggregation and ultimately cell demise.Proteinopathies include, for example, tauopathies, synucleopathies, anddisorders characterized by the aggregation of amyloid-beta peptides.Proteinopathies may also include prion disease and amyloidosis.Proteinopathies may be associated with a structurally abnormal proteinselected from tau, synuclein, amyloid beta, or a combination thereof.Proteinopathies may be associated with a misfolded or aggregated proteinselected from tau, synuclein, amyloid beta, or a combination thereof.

a. Tau

In some embodiments, the compounds or salts thereof as detailed hereininhibit or disrupt the aggregation of tau protein, to treattauophathies. Tau is a protein that associates with and stabilizesmicrotubules. Tau may also be referred to as microtubule associatedprotein tau (MAPT). Tau proteins may also interact with tubulin tostabilize microtubules and promote tubulin assembly into microtubules.There are six isoforms of Tau. Tau proteins are abundant in neurons ofthe central nervous system and are also expressed at very low levels incentral nervous system (CNS) astrocytes and oligodendrocytes.

Tau protein may be phosphorylated by a host of kinases. Phosphorylationof tau is developmentally regulated. Excessive phosphorylation(hyperphosphorylation) or abnormal phosphorylation of tau may result indisruption of microtubule organization, accumulation, and aggregation oftau proteins. In some embodiments tau aggregates do not functionproperly. For example, tau aggregates may not stabilize microtubulesproperly.

Tau aggregates include, for example, PHF-tau (paired helical filament),NFTs (neurofibrillary tangles), and gliofibrillary tangles. Tauaggregates may also be described as monomeric, or high molecular weightmultimers. Tau aggregates may be insoluble. Tau aggregates may bepresent in the brain. Tau proteins may be deposited in the form ofinclusion bodies within swollen neurons. Aggregation of tau intooligomeric species may lead to various pathologies called tauopathiesand may be a major contributor to disease progression.

Tauopathies are a class of neurodegenerative diseases associated withthe pathological aggregation of tau protein. Tauopathies include, forexample, Alzheimer's disease (AD), Parkinson's disease, Huntington'sdisease, neuronal loss, cognitive defect, primary age-related tauopathy(PART)/Neurofibrillary tangle-predominant senile dementia, chronictraumatic encephalopathy including dementia pugilistica, progressivesupranuclear palsy, Pick's Disease, corticobasal degeneration, someforms of frontotemporal lobar degeneration, frontotemporal dementia andparkinsonism linked to chromosome 17, Lytico-Bodig disease(Parkinson-dementia complex of Guam), ganglioglioma, gangliocytoma,meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosingpanencephalitis, lead encephalopathy, tuberous sclerosis,Hallervorden-Spatz disease, and lipofuscinosis. In some embodiments, thetauopathy comprises Alzheimer's disease (AD).

b. Synuclein

In some embodiments, the compounds or salts thereof as detailed hereininhibit or disrupt the aggregation of synuclein, to treatsynucleinopathies. Synucleins are a family of proteins common tovertebrates. Synucleins are primarily expressed in neural tissue and incertain tumors. Synucleins have a highly conserved alpha-helicallipid-binding motif. Synucleins include, for example, alpha-synuclein,beta-synuclein, and gamma-synuclein proteins. Alpha-synuclein may befound in the heart, muscle, brain, and other tissues. In the brain,alpha-synuclein may be found at the tips of neurons at the presynapticterminal. Alpha-synuclein can interact with phospholipids and proteins.Alpha-synuclein can directly bind to lipid membranes by associating withthe negatively charged surfaces of phospholipids. Alpha-synuclein mayplay a role in maintaining a supply of synaptic vesicles in presynapticterminals by clustering synaptic vesicles. Alpha-synuclein may helpregulate the release of dopamine. Alpha-synuclein may interact withtubulin and have activity as a microtubule-associated protein, similarto tau. In some embodiments, the multiple forms of alpha-synuclein areselected from insoluble, monomeric, and high molecular weight multimers.Expression of gamma-synuclein in breast tumors may be a marker for tumorprogression.

Synucleinopathies are neurodegenerative diseases characterized by theabnormal accumulation of aggregates of synucleins such as aggregates ofalpha-synuclein in, for example, neurons, nerve fibres, or glial cells.Synucleinopathies include, for example, Parkinson's Disease, dementiawith Lewy bodies, neuroaxonal dystrophies, and multiple system atrophy.In some embodiments, synucleinopathies may overlap with tauopathies,potentially because of an interaction between alpha-synuclein and tau.

c. Amyloid-Beta Peptides

In some embodiments, the compounds or salts thereof as detailed hereininhibit or disrupt the aggregation of amyloid-beta peptides, to treatdisorders such as Alzheimer's disease. Amyloid-beta peptides (alsoreferred to as “amyloid beta”, “A-beta”, “Abeta,” or “Aβ”) are peptidesthat are found in the brain. The normal function of amyloid-betapeptides may include activation of kinase enzymes, protection againstoxidative stress, regulation of cholesterol transport, activity as atranscription factor, and anti-microbial activity (which may beassociated with a pro-inflammatory activity of amyloid-beta peptidespeptides). Amyloid-beta peptides are formed after sequential cleavage ofthe amyloid precursor protein (APP), which is a transmembraneglycoprotein. APP can be cleaved by the proteolytic enzymes α-, β- andγ-secretase. Amyloid-beta peptide is generated by successive action ofthe β- and γ-secretases. The γ-secretase, which produces the C-terminalend of the amyloid-beta peptide, cleaves within the transmembrane regionof APP and can generate a number of isoforms of 30 to 51 amino acidresidues in length. In some embodiments, amyloid-beta peptide is 36 to43 amino acids in length. The most common isoforms of the amyloid-betapeptide are 40 amino acids in length (Aβ40) and 42 amino acids in length(Aβ42). The longer form Aβ42 is typically produced by cleavage thatoccurs in the endoplasmic reticulum, while the shorter form Aβ40 isproduced by cleavage in the trans-Golgi network. The Aβ40 form is themore common of the two forms, but Aβ42 may be more fibrillogenic.

Amyloid-beta peptides can aggregate to form flexible soluble oligomersor aggregates, which may exist in several forms. Certain misfoldedoligomers (known as “seeds”) may induce other amyloid-beta peptides toalso take the misfolded oligomeric form, leading to a chain reactionakin to a prion infection. Amyloid-beta aggregates are toxic to nervecells. Amyloid-beta aggregates may induce tau to misfold. Amyloid-betapeptides are also the main component of amyloid plaques, which areextracellular deposits found in the brains of patients with Alzheimer'sdisease. Similar plaques appear in some variants of Lewy body dementiaand in inclusion body myositis (a muscle disease), while amyloid-betapeptides can also form the aggregates that coat cerebral blood vesselsin cerebral amyloid angiopathy. Amyloid plaques are composed of a tangleof regularly ordered fibrillar aggregates called amyloid fibers, whichis a protein fold shared by other peptides such as the prions associatedwith protein misfolding diseases. Soluble oligomeric forms of theamyloid-beta peptide may be causative agents in the development ofAlzheimer's disease. Aggregation of amyloid-beta may lead to Alzheimer'sdisease. In Alzheimer's disease patients, two distinct types offibrillar protein aggregates are commonly found in brain samples:amyloid plaques comprising deposits of amyloid-beta protein (Aβ) andneurofibrillary tangles consisting of the microtubule-associated proteintau. Genetic and neuropathologic studies suggest that the accumulationof amyloid plaques and/or neurofibrillary tangles may be central to thepathogenesis of Alzheimer's disease.

4. METHODS

a. Methods Of Treating A Neurodegenerative Disease

Provided herein are methods of treating a neurodegenerative disease in asubject. The method may include administering to the subject aneffective amount of a compound or salt or composition as detailedherein. The compounds as detailed herein may disrupt, reduce, inhibit,or prevent the aggregation of molecules such as tau protein, synuclein,and amyloid-beta peptides, or a combination thereof, to treat theneurodegenerative disease. The subject may be diagnosed with or at riskof developing neurodegenerative disease. The subject may be undergoingother forms of treatment for neurodegenerative disease.

In some embodiments, provided is a method for treating Alzheimer'sdisease in a subject. The method may comprise administering atherapeutically effective amount of the disclosed compounds or salts orcompositions to the subject. The subject may be diagnosed with or atrisk of developing Alzheimer's disease. The subject may be undergoingother forms of treatment for Alzheimer's disease.

b. Methods of Reducing or Eliminating an Aggregated Protein

Provided herein are methods of reducing or eliminating an aggregatedprotein in a subject. The method may include administering to thesubject an effective amount of a compound or salt or composition asdetailed herein. The compounds as detailed herein may disrupt, reduce,inhibit, or prevent the aggregation of molecules including tau protein,synuclein, and amyloid-beta peptides, or a combination thereof. Thesubject may be diagnosed with or at risk of developing neurodegenerativedisease. The subject may be undergoing other forms of treatment forneurodegenerative disease.

Further provided are methods of reducing or inhibiting proteinaggregation in a subject. The method may include administering to thesubject an effective amount of a compound or salt or composition asdetailed herein. The protein may comprise at least one of tau,synuclein, amyloid-beta, or a combination thereof. The subject may bediagnosed with or at risk of developing neurodegenerative disease. Thesubject may be undergoing other forms of treatment for neurodegenerativedisease.

Protein aggregation or fibrillation may be reduced or inhibited relativeto a control. In some embodiments, protein aggregation or fibrillationis reduced or inhibited by at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 55%, at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, at least about 95%, at least about97%, at least about 98%, or at least about 99% relative to a control. Insome embodiments, the control is a healthy subject or sample therefrom,a diseased subject or sample therefrom, a subject or sample therefromwithout or prior to treatment, or a subject or sample therefrom at anypoint earlier in treatment. For example, the disclosed compounds orsalts or compositions may reduce or inhibit amyloid-beta fibrillation.In other embodiments, the disclosed compounds or salts or compositionsmay reduce or inhibit tau protein aggregation. In other embodiments, thedisclosed compounds or salts or compositions may reduce or inhibitaggregation of synuclein.

5. EXAMPLES Example 1 Synthesis of HW-C-9

All Fmoc protected α-amino acids and Rink amide resin (0.7 mmol/g,200-400 mesh) were purchased from Chem-Impex International, Inc. (WoodDale, Ill.). TentaGel MB NH2 resin (0.3 mmol/g, 140-170 μm) waspurchased from RaPP Polymere GmbH (Tubingen, Germany). All the othersolvents and reagents were purchased from either Sigma-Aldrich (St.Louis, Mo.) or Fisher Scientific (Hampton, N.H.). NMR data for buildingblocks was obtained on a Varian UnityInova400 spectrometer. Highresolution masses of building blocks were determined on an Agilent 6540Liquid Chromatography/Quadrupole Time-of Flight mass spectrometer.Masses of γ-AApeptides were obtained on an Applied Biosystems 4700Proteomics Analyzer. MS/MS analysis was carried out with a Thermo LTQOrbitrap XL. Solid phase synthesis was conducted in peptide synthesisvessels on a Burrell Wrist-Action shaker. γ-AApeptides were analyzed andpurified on a Waters Breeze 2 HPLC system, and then lyophilized on aLabcono lyophilizer.

Solid phase synthesis was conducted on Rink amide resin (0.7 mmol/g) inpeptide synthesis vessels on a Burrell Wrist-Action shaker (FIG. 2). 100mg resin (0.07 mmol) was treated with 3 mL 20% Piperidine/DMF solutionfor 15 min (×2) to remove Fmoc protecting group. The solution wasdrained and beads were washed with DCM (3×3 mL) and DMF (3×3 mL). Asolution of γ-AApeptide building block (2 equiv.) (Niu, et al. Chemicalcommunications, Cambridge, England 2011, 47, 12197-12199; Niu, et al.Org. Biomol. Chem. 2011, 9, 6604-6609; Niu, et al. New Journal ofChemistry 2011, 35, 542-545; Wu, et al. Chem. Sci. 2012, 3 2570-2575;Wu, et al. Submitted), HOBt (38 mg, 0.28 mmol), and DIC (44 μL, 0.28mmol) in 3 mL DMF was shaken for 5 min, and then added to the resin in apeptide synthesis vessel. The mixture was allowed to react at roomtemperature for 6 h and drained. The beads were washed with DCM (3×3 mL)and DMF (3×3 mL), followed by a capping reaction with 500 μL aceticanhydride in 3 mL Pyridine. After washing with DMF (3×3 mL) and DCM (3×3mL), to the beads were added Pd(PPh₃)₄ (8 mg, 0.007 mmol) and Me₂NH.BH₃(25 mg, 0.42 mmol) in 3 mL DCM (Gomez-Martinez, et al. J. Chem. Soc.Perk. T 1, 1999, 2871-2874). The alloc deprotection reaction was shakenfor 10 min and repeated one more time. The beads were washed with DCMand DMF, followed by the reaction with acid chloride (4 equiv.) andDIPEA (6 equiv.) in 3 mL DCM for 30 min (×2) or with carboxylic acid (4equiv.), HOBt (8 equiv.), and DIC (8 equiv.) for 4 h (×2).

The previous steps were repeated until the desired sequences wereobtained. Examples of N-Alloc protected γ-AApeptide building blocks andacylating agents (carboxylic acids and acyl chlorides) that may be usedin the preparation of γ-AApeptides are shown in FIG. 3. After that, theresin were washed with DCM and dried in vacuo. Peptide cleavage was donein a 4 mL vial by treating resin with TFA/H₂O/TIS (95/2.5/2.5) for 2 h.The solvent was evaporated and the crude was analyzed and purified on ananalytical (1 mL/min) and a preparative (20 mL/min) Waters HPLC systems,respectively. 5% to 100% linear gradient of solvent B (0.1% TFA inacetonitrile) in solvent A (0.1% TFA in water) over 40 min was used. TheHPLC traces were detected at 215 nm. The products were confirmed on anApplied Biosystems 4700 Proteomics Analyzer. Then, the desired fractionswere collected and lyophilized.

Example 2 Effect of HW-C-9 on Aβ42

The effect of HW-C-9 on Aβ42 was analyzed using the Thioflavin T (ThT)spectroscopic assay. Thioflavin T (ThT) is a benzothiazole salt obtainedby the methylation of dehydrothiotoluidine with methanol in the presenceof hydrochloric acid. ThT was used as a dye to visualize and quantifythe presence or fibrilization of misfolded protein aggregates. Briefly,HW-C-9 in Tris Buffered Saline (TBS, pH 7.5) containing 10 μM ThT wasadded into a black 96 well plate. Aβ42 protein monomer was freshlythawed and used to make a stock 5 μM solution in TBS. An equal volume ofAβ42 solution was added to each well to a final concentration of 2.5 μMAβ42 and incubated at 37° C. Time-dependent fluorescence change wasmonitored by a Synergy 2 plate reader at an excitation wavelength of 440nm and emission at 482 nm. The fluorescence intensity of ThT wasmeasured over time, as ThT changed fluorescence intensity upon bindingto the Aβ42 protein aggregates. 100% aggregation was defined as thefluorescence change of 2.5 μM Aβ42 in TBS buffer containing 5 μM ThTafter 24 hours.

Results are shown in FIG. 4. In FIG. 4, C1 is 1 μM of HW-C-9, C3 is 5 μMof HW-C-9, and C4 is 10 μM of HW-C-9. Aβ42 was present in all samples ata concentration of 5 μM. The top curve (red line, “Agg”) is theAβ42-only control. The results indicated that HW-C-9 can inhibit Aβ42aggregation at all concentrations tested.

Example 3 Effect of HW-C-9 on Tau Protein

The effect of HW-C-9 on recombinant human tau protein was analyzed usingthe ThT assay, as detailed in Example 2, but with tau protein in placeof Aβ42. Results are shown in FIG. 5. In FIG. 5, C1 is 100 μM of HW-C-9,C2 is 50 μM of HW-C-9, C3 is 20 μM of HW-C-9, C4 is 10 μM of HW-C-9, andC5 is 1 μM of HW-C-9. Tau was present in all samples at a concentrationof 10 μM. The top curve (red line with black triangle, “Aggregationcontrol”) is the Tau-only control. The results indicated that HW-C-9 caninhibit aggregation of tau protein at all concentrations tested.

Example 4 Effect of HW-C-9 on Aβ42

The effect of HW-C-9 on Aβ42 was analyzed, with HW-155-1 used as acontrol. HW-155-1 is a monomer of HW-C-9 and has the structure shownbelow:

Results from the experiment are shown in FIG. 6A and FIG. 6B. Shown inFIG. 6A is a Western blot of Aβ42, wherein lane 1 is 20 μM of Aβ, lane 2is 40 μM of HW-155-1 as a control and 20 μM of Aβ, and lane 3 is 40 μMof HW-C-9 and 20 μM of Aβ. Shown in FIG. 6B on the left is mouse braintissue incubated overnight with and without 25 μM of HW-C-9, and thenimmunohistochemically stained with Aβ42 antibodies. On the right of FIG.6B is a graphical quantification of the density and strength of theantibody stains. The results indicated that HW-C-9 can inhibitaggregation of Aβ42 and remove amyloid plaques.

Example 5 Effect of HW-C-9 on Synuclein

The effect of HW-C-9 on synuclein was analyzed with a Western blot.Results are shown in FIG. 7, wherein lane 1 is human recombinantalpha-synuclein (stained with goat anti-human alpha-synuclein antibody)without aggregation as a control, lane 2 is human recombinantalpha-synuclein (stained with goat anti-human alpha-synuclein antibody)aggregated for 7 days, and lane 3 is human recombinant alpha-synuclein(stained with goat anti-human alpha-synuclein antibody) aggregated for 7days in the presence of 25 μg/mL of HW-C-9. The results indicated thatHW-C-9 can inhibit aggregation of alpha-synuclein.

The foregoing description of the specific aspects will so fully revealthe general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific aspects, without undueexperimentation, without departing from the general concept of thepresent disclosure. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed aspects, based on the teaching and guidance presented herein.It is to be understood that the phraseology or terminology herein is forthe purpose of description and not of limitation, such that theterminology or phraseology of the present specification is to beinterpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present disclosure should not be limited byany of the above-described exemplary aspects, but should be defined onlyin accordance with the following claims and their equivalents.

All publications, patents, patent applications, and/or other documentscited in this application are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent, patent application, and/or other document wereindividually indicated to be incorporated by reference for all purposes.

For reasons of completeness, various aspects of the invention are setout in the following numbered clauses:

Clause 1. A compound selected from the following:

or a pharmaceutically acceptable salt thereof.

Clause 2. A pharmaceutical composition comprising the compound or saltof clause 1, and a carrier.

Clause 3. A method of treating a neurodegenerative disease in a subject,the method comprising administering to the subject the compound or saltof clause 1 or the composition of clause 2.

Clause 4. The method of clause 3, wherein the neurodegenerative diseaseis selected from Alzheimer's Disease (AD), amyotrophic lateral sclerosis(ALS), Parkinson's Disease (PD), Huntington's Disease, prion disease,motor neuron disease, spinocerebellar ataxia, spinal muscular atrophy,neuronal loss, cognitive defect, primary age-related tauopathy(PART)/Neurofibrillary tangle-predominant senile dementia, chronictraumatic encephalopathy including dementia pugilistica, dementia withLewy bodies, neuroaxonal dystrophies, and multiple system atrophy,progressive supranuclear palsy, Pick's Disease, corticobasaldegeneration, some forms of frontotemporal lobar degeneration,frontotemporal dementia and parkinsonism linked to chromosome 17,Lytico-Bodig disease (Parkinson-dementia complex of Guam),ganglioglioma, gangliocytoma, meningioangiomatosis, postencephaliticparkinsonism, subacute sclerosing panencephalitis, lead encephalopathy,tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

Clause 5. The method of clause 4, wherein the neurodegenerative diseaseis selected from Alzheimer's Disease (AD) and Huntington's Disease.

Clause 6. A method of reducing or eliminating an aggregated protein in asubject, the method comprising administering to the subject the compoundor salt of clause 1 or the composition of clause 2, wherein theaggregated protein comprises at least one of tau, synuclein,amyloid-beta, or a combination thereof.

Clause 7. The method of clause 6, wherein the synuclein comprisesalpha-synuclein.

Clause 8. A method of reducing or inhibiting protein aggregation in asubject, the method comprising administering to the subject an effectiveamount of the compound or salt of clause 1 or the composition of clause2, wherein the protein comprises at least one of tau, synuclein,amyloid-beta, or a combination thereof.

Clause 9. The method of clause 8, wherein the synuclein comprisesalpha-synuclein.

The invention claimed is:
 1. A method of preparing compound HW-C-9having the following structure:

comprising: reacting an amino-substituted resin represented by thefollowing structure:

wherein

represents a resin; with a compound of Formula (A-i):

to form a compound of Formula (A-ii):

reacting the compound of Formula (A-ii) to form a compound of Formula(A-iii):

reacting the compound of Formula (A-iii) with a compound of Formula(A-iv):

to form a compound of Formula (A-v):

reacting the compound of Formula (A-v) to form a compound of Formula(A-vi):

and reacting the compound of Formula (A-vi) to form HW-C-9; wherein eachoccurrence of P¹ is independently selected from the group consisting of:H, allyloxycarbonyl, benzyloxycarbonyl, carbobenzyloxy,para-methoxybenzyl carbonyl, tert-butyloxycarbonyl,9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamoyl,para-toluenesulfonyl, para-methoxybenzyl, 3,4-dimethyoxybenzyl,para-methoxyphenyl, nitrobenzenesulfonyl, methanesulfonyl,trifluoromethanesulfonyl, bromobenzenesulfonyl, and trichloroethylchloroformate.
 2. The method of claim 1, wherein reacting the compoundof Formula (A-vi) to form HW-C-9 further comprises reacting the compoundof Formula (A-vi) with a compound of Formula (I-i):

to form a compound of Formula (I-ii):

wherein P¹ and P² are independently selected from the group consistingof: H, allyloxycarbonyl, benzyloxycarbonyl, carbobenzyloxy,para-methoxybenzyl carbonyl, tert-butyloxycarbonyl,9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamoyl,para-toluenesulfonyl, para-methoxybenzyl, 3,4-dimethyoxybenzyl,para-methoxyphenyl, nitrobenzenesulfonyl, methanesulfonyl,trifluoromethanesulfonyl, bromobenzenesulfonyl, and trichloroethylchloroformate.
 3. The method of claim 2, wherein reacting the compoundof Formula (A-vi) to form HW-C-9 further comprises: reacting thecompound of Formula (I-ii):

to form a compound of Formula (I-iii):

wherein P¹ and P² are independently selected from the group consistingof: H, allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate.
 4. The method of claim 3, wherein reactingthe compound of Formula (A-vi) to form HW-C-9 further comprises:reacting the compound of Formula (I-iii):

with (CH₃)₂CH₂C(O)Cl or (CH₃)₂CH₂C(O)OH; to form a compound of Formula(I-iv):

wherein P¹ is selected from the group consisting of: H,allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate.
 5. The method of claim 4, wherein reactingthe compound of Formula (A-vi) to form HW-C-9 further comprises:reacting the compound of Formula (I-iv):

wherein P¹ is selected from the group consisting of: H,allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate; to form a compound of Formula (I-v):


6. The method of claim 5, wherein reacting the compound of Formula(A-vi) to form HW-C-9 further comprises reacting the compound of Formula(I-v)

with a compound of Formula (II-i):

to form a compound of Formula (II-ii):

wherein P¹, P², and P³ are independently selected from the groupconsisting of: H, allyloxycarbonyl, benzyloxycarbonyl, carbobenzyloxy,para-methoxybenzyl carbonyl, tert-butyloxycarbonyl,9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamoyl,para-toluenesulfonyl, para-methoxybenzyl, 3,4-dimethyoxybenzyl,para-methoxyphenyl, nitrobenzenesulfonyl, methanesulfonyl,trifluoromethanesulfonyl, bromobenzenesulfonyl, and trichloroethylchloroformate.
 7. The method of claim 6, wherein reacting the compoundof Formula (A-vi) to form HW-C-9 further comprises: reacting thecompound of Formula (II-ii):

to form a compound of Formula (II-iii):

wherein P¹ and P³ are independently selected from the group consistingof: H, allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate.
 8. The method of claim 7, wherein reactingthe compound of Formula (A-vi) to form HW-C-9 further comprises:reacting the compound of Formula (II-iii):

with (CH₃)₂CH₂C(O)Cl or (CH₃)₂CH₂C(O)OH; to form a compound of Formula(II-iv):

wherein P¹ and P³ are independently selected from the group consistingof: H, allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate.
 9. The method of claim 8, wherein reactingthe compound of Formula (A-vi) to form HW-C-9 further comprises:reacting the compound of Formula (II-iv):

wherein P¹ and P³ are independently selected from the group consistingof: H, allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate; to form a compound of Formula (II-v):

wherein P³ is selected from the group consisting of: H,allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate.
 10. The method of claim 9, whereinreacting the compound of Formula (A-vi) to form HW-C-9 further comprisesreacting the compound of Formula (II-v):

wherein P³ is selected from the group consisting of: H,allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate; to form a compound of Formula (III-v):

wherein P³ is selected from the group consisting of: H,allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate.
 11. The method of claim 10, whereinreacting the compound of Formula (A-vi) to form HW-C-9 further comprisesreacting the compound of Formula (III-v):

wherein P³ is selected from the group consisting of: H,allyloxycarbonyl, carbobenzyloxy, para-methoxybenzyl carbonyl,tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl,benzyl, carbamoyl, para-toluenesulfonyl, para-methoxybenzyl,3,4-dimethyoxybenzyl, para-methoxyphenyl, nitrobenzenesulfonyl,methanesulfonyl, trifluoromethanesulfonyl, bromobenzenesulfonyl, andtrichloroethyl chloroformate; to form a compound of Formula (IV-v):

wherein P¹ and each occurrence of P³ are independently selected from thegroup consisting of: H, allyloxycarbonyl, carbobenzyloxy,para-methoxybenzyl carbonyl, tert-butyloxycarbonyl,9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamoyl,para-toluenesulfonyl, para-methoxybenzyl, 3,4-dimethyoxybenzyl,para-methoxyphenyl, nitrobenzenesulfonyl, methanesulfonyl,trifluoromethanesulfonyl, bromobenzenesulfonyl, and trichloroethylchloroformate.
 12. The method of claim 11, wherein each occurrence of P²is allyloxycarbonyl.
 13. The method of claim 11, wherein each occurrenceof P¹ is 9-fluorenylmethyloxycarbonyl.
 14. The method of claim 11,wherein each occurrence of P³ is tert-butyloxycarbonyl.
 15. The methodof claim 11, wherein reacting the compound of Formula (A-i) to form thecompound of Formula (A-ii), reacting the compound of Formula (A-iii) toform the compound of Formula (A-v), reacting the compound of Formula(A-vi) to form the compound of Formula (I-ii), and reacting the compoundof Formula (I-v) to form the compound of Formula (II-ii) are performedin the presence of 1-hydroxybenzotriazole and diisopropylcarbodiimide.16. The method of claim 11, wherein reacting the compound of Formula(I-iii) to form the compound of (I-iv) and reacting the compound ofFormula (II-iii) to form the compound of (II-iv) are performed with(CH₃)₂CH₂C(O)Cl.
 17. The method of claim 11, wherein reacting thecompound of Formula (I-iii) to form the compound of (I-iv) and reactingthe compound of Formula (II-iii) to form the compound of (II-iv) areperformed with (CH₃)₂CH₂C(O)OH.
 18. The method of claim 11, whereinreacting the compound of Formula (A-vi) to form HW-C-9 further comprisesreacting the compound of Formula (IV-v) with trifluoroacetic acid toform HW-C-9.